Venetoclax + HMA for Acute Myeloid Leukemia

Recruiting at 216 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A4 inducers

Disqualifiers: Pregnancy, Breastfeeding, Uncontrolled infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 31

147 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for people with acute myeloid leukemia (AML), a type of blood cancer, who have a specific genetic mutation called FLT3. Researchers aim to determine if adding a drug called gilteritinib to the usual treatment of azacitidine (Vidaza) and venetoclax (Venclexta) can help achieve a deeper remission, where cancer is not detectable. The trial targets older adults or those unsuitable for intensive treatments. Individuals diagnosed with AML and the FLT3 mutation who have not yet started treatment may find this trial suitable. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on a strong CYP3A4 inducing drug, as it may interfere with the trial medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of azacitidine and venetoclax is generally well-tolerated by patients with acute myeloid leukemia (AML). However, some patients experienced serious side effects, such as sepsis, a potentially life-threatening infection, leading to changes in dosing to ensure safety. Long-term studies indicate that this combination helps patients who cannot undergo intensive treatment live longer.

For the combination of azacitidine, venetoclax, and gilteritinib, studies show promising results regarding patient response and survival rates. Researchers aim to find the best dose and ensure safety. So far, this combination has shown high response rates in patients with certain gene mutations in AML, although detailed safety information is still being gathered. As this treatment remains under investigation, ongoing trials continue to assess its safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute myeloid leukemia (AML) because they combine standard therapies like azacitidine with new approaches using venetoclax and gilteritinib. Venetoclax is a BCL-2 inhibitor, which helps to trigger the death of cancer cells, offering a different mechanism than traditional chemotherapy. Gilteritinib targets specific mutations in AML cells, potentially improving outcomes for patients with those genetic profiles. This combination strategy aims to enhance treatment effectiveness and potentially lead to faster remission compared to conventional treatment options.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that combining azacitidine and venetoclax, which participants in this trial may receive, helps patients with acute myeloid leukemia (AML) who cannot undergo intensive treatment live longer. In one study, 29.9% of patients achieved complete remission, with no cancer detected. Another treatment option in this trial involves adding gilteritinib to azacitidine and venetoclax, which has demonstrated even better results for patients with AML who have FLT3 mutations. This combination led to high response rates and proved effective at a genetic level. Overall, these treatments hold promise for improving outcomes in AML patients. ^{1 2 3 5 6}

Who Is on the Research Team?

Jessica K Altman

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for older adults or those unfit for intensive therapy, aged 60+ or younger with specific health considerations. Participants must have AML with FLT3 mutations, no prior treatment with hypomethylating agents or FLT3 inhibitors, and not be pregnant or breastfeeding. They should agree to use effective contraception.

Inclusion Criteria

I am HIV-positive, on treatment, and my viral load is undetectable.

Patient must not breastfeed during treatment and for a specified period after treatment ends

I can understand and am willing to sign the consent form, or I have someone who can do it for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive azacitidine and venetoclax, with or without gilteritinib, for up to 2 cycles or until remission

8 weeks

Multiple visits for drug administration and monitoring

Consolidation

Patients continue treatment with azacitidine and venetoclax, with or without gilteritinib, for 2 years

2 years

Regular visits every 28 days for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 10 years

Every 3 months if < 2 years from registration, every 6 months if 2-5 years from registration

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Gilteritinib
• Venetoclax

Trial Overview The study compares usual AML treatment (azacitidine + venetoclax) against a combination of azacitidine, venetoclax, and gilteritinib. It aims to see if adding gilteritinib increases the percentage of patients achieving deeper remission compared to the standard approach.

How Is the Trial Designed?

Group I: Regimen 3 (azacitidine, venetoclax, gilteritinib) Experimental Treatment 6 Interventions

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28, and gilteritinib PO on days 8-21 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-14 and gilteritinib PO on days 8-21 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial.

Group II: Regimen 2 (azacitidine, venetoclax, gilteritinib) Experimental Treatment 6 Interventions

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax and gilteritinib PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-5, venetoclax PO on days 1-7 and gilteritinib PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial.

Group III: Regimen 1 (azacitidine, venetoclax) Experimental Treatment 5 Interventions

INDUCTION: Patients receive azacitidine IV or SC on days 1-7 of each cycle and venetoclax PO on days 1-28 of each cycle. Treatment repeats every 28 days for up to 2 cycles or until patient achieves remission, whichever comes first, in the absence of disease progression or unacceptable toxicity. CONSOLIDATION: Patients receive azacitidine IV or SC on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow biopsy and aspiration as well as blood sample collection on the trial.

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

Citations

1. venclextahcp.com venclextahcp.com/aml/efficacy/ven-aza/survival-results.html

VEN+AZA: Overall survival (OS) data from the VIALE-A trial Fatal adverse reactions occurred in 23% of patients who received VENCLEXTA in combination with azacitidine, with the most frequent (≥2%) being pneumonia (4%), ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38343151/

Long-term follow-up of VIALE-A: Venetoclax and ... Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive ...

3. ashpublications.org ashpublications.org/blood/article/145/11/1126/534406/Efficacy-and-safety-of-venetoclax-plus-azacitidine

Efficacy and safety of venetoclax plus azacitidine for patients ... Among 107 patients treated with venetoclax plus azacitidine at the RP2D, 29.9% (n = 32; 95% CI, 21.4-39.5) achieved a best response of CR, and ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04161885

NCT04161885 | A Study Evaluating Safety and Efficacy of ... The main objective of this study is to evaluate the efficacy of venetoclax in combination with azacitidine to improve Overall Survival (OS) in Acute Myeloid ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11707511/

Venetoclax-Based Combination Regimens in Acute Myeloid ... Of the patients receiving azacitidine–venetoclax combination, 25% had secondary AML and 36% demonstrated poor cytogenetic risk. With a median follow-up of 20.5 ...

6. news.abbvie.com news.abbvie.com/2020-03-23-AbbVie-Announces-Positive-Topline-Results-from-Phase-3-Trial-of-VENCLEXTA-R-venetoclax-in-Combination-with-Azacitidine-in-Patients-with-Acute-Myeloid-Leukemia-AML

AbbVie Announces Positive Topline Results from Phase 3 ... The Phase 3 VIALE-A study evaluated the efficacy and safety of venetoclax in combination with azacitidine compared with placebo in combination with azacitidine.